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  Prescribing in pregnancy

P. C. RUBIN

INTRODUCTION

Safe and effective prescribing during pregnancy requires an awareness of what drugs can do to the fetus and of what pregnancy can do to drugs. Concern naturally centres on the possible harm which drugs may cause to the developing fetus, but it is sometimes overlooked that pregnancy can produce clinically important changes in drug disposition. While knowledge in most therapeutic areas has grown rapidly in recent decades, information on the use of drugs in pregnancy has developed sporadically, with case reports being more usual than large, prospective clinical trials. The reasons are not surprising and largely relate to concern about causing harm to the developing fetus.

Thalidomide is a name inescapably associated with prescribing in pregnancy. Drug-induced fetal abnormality did not begin with thalidomide: Hippocrates appeared to recognize that drugs were best avoided in the first trimester. However, the scale of the thalidomide tragedy brought to the general public for the first time the realization that drugs could harm the developing baby. Thalidomide was marketed in Germany in 1956 and subsequently in other countries as a sedative and hypnotic which had the particular attraction of being safe in overdose. Indeed, the drug was considered so safe that in some countries it was available without prescription. Then in 1960 to 1961 Germany experienced what amounted to an epidemic of phocomelia: a birth defect involving absence of the long bones with hands and feet being attached directly to the trunk. What had previously been an extremely rare condition (no cases had been reported in the 10 years to 1959) was being seen almost commonly. Various causes—viral, radioactivity, food preservatives—were considered as culprits until one doctor retrospectively questioned his patients and found that 20 per cent had taken thalidomide in early pregnancy. On repeat questioning, asking specifically about the drug, 50 per cent admitted taking thalidomide, many having not mentioned it before since the drug was so obviously innocent. In fact, around 80 per cent of women who took thalidomide in the first trimester had a deformed baby. More than 10 000 such babies had been born before the drug was removed from the market.

The thalidomide experience had far-reaching ramifications. Drug regulation as we know it stems largely from the disaster. Doctors and their patients recognized that there is no such thing as a safe drug. In addition, the pharmaceutical industry has largely avoided obtaining systematic information on drug use in pregnancy. The reasons are obvious and understandable, but for the prescribing doctor the statement that ‘the safety of this drug in pregnancy has not been established’ is not helpful when faced with a woman who is, or may become, pregnant. A drug is unlikely to be studied comprehensively during pregnancy unless it is known to be safe, and its safety cannot be definitely established unless large studies have been performed. Thus information tends to accumulate through inadvertent use when pregnancy is not suspected, or intentional use in a few cases here and there when the risks of the disease being treated are considered to outweigh any possible harm from the drug. Therapeutic management decisions must frequently be made with the help of limited information.

The effect of drugs on the fetus

A drug can harm the fetus only if it crosses the placenta, but most drugs do. The placenta offers a lipid barrier to the transfer of drugs. The rate at which a drug crosses from mother to baby will depend on its lipophilicity and polarity. However, with the exception of drugs administered acutely around the time of delivery, the rate of transfer is of little importance, and for any course of drug treatment it should be assumed that transfer will occur. The only notable exception is heparin, a molecule of such size and polarity that it does not cross to the fetus.

Drugs can adversely affect the developing fetus in different ways depending on the gestation at which exposure occurs. For this reason it is appropriate to consider organogenesis, fetal growth and development, the breast-fed infant, and childhood growth and development separately.

Prescribing in the first trimester

Organogenesis occurs between 18 and 55 days of gestation and it is during this time that drugs can cause anatomical defects. Some drugs that are definitely teratogenic in the human are listed in  Table 1 636. A drug can cause a teratogenic effect only if it is present in the embryo during organogenesis. Even a definite teratogen will not cause a structural defect if it is given following this period. These seemingly obvious statements become relevant in pre-pregnancy counselling and in providing advice when exposure to a possible teratogen has occurred during pregnancy. Being present in the embryo during organogenesis is not necessarily synonymous with being prescribed during this period. The retinoids are stored in adipose tissue and released slowly, so a teratogenic effect can occur many weeks after the course of treatment has been completed.

It is important to recognize that these drugs will not be teratogenic in all cases: on the contrary, most first trimester exposures will not harm the baby. The risk of fetal malformation following anticonvulsant use in the first trimester is between 5 and 10 per cent. Figures vary widely with regard to warfarin, abnormality rates from 2 to 25 per cent being quoted in different studies. Lithium is teratogenic in very few exposures, while the retinoids carry a very substantial risk. Figures are not available for danazol. Clearly there is more to drug-induced fetal abnormality than simply the drug. Some reports have claimed a direct relationship between dose and fetal abnormality. While some studies have shown a trend in this direction, the dose does not seem to be a prominent factor in human therapeutics, since epileptic women receiving anticonvulsants have been reported to ‘run true’ in successive pregnancies. If the first pregnancy ended with a normal baby, subsequent ones often (but not always) do so as well and vice versa.

Many of the abnormalities caused by these drugs can be detected by detailed ultrasound scanning at 18 weeks' gestation. However, the defects caused by warfarin involve mainly soft tissue and do not fall into this category.

 Table 1 636 is not comprehensive and includes only those drugs encountered in general medical practice. Some drugs used in specialist areas are teratogenic, for example several drugs used in cancer chemotherapy (see  Section 6 14). Many more drugs may be teratogenic in a small percentage of exposures, but definitive information is not available because both prediction and detection of human teratogens is difficult. Predicting the effect of a drug in the human usually depends on studying its pharmacology in experimental animals. This is not fruitful in the area of teratogenesis because species variation is so great. For example, thalidomide is a teratogen only in primates, while lithium causes cardiac abnormalities in humans at doses that produce no effect in the rat. Detecting teratogenic effects is complicated by the normal occurrence of fetal abnormalities in around 2 per cent of babies. If a drug is teratogenic very occasionally, it can be very difficult to distinguish its effects from naturally occurring defects without a very sophisticated surveillance system. Information on drug-induced fetal abnormality comes from case reports, case studies, and epidemiological studies.

Case reports are a two-edged sword. Describing a single association between a drug and a fetal abnormality can be very useful in first identifying a real problem: warfarin was first linked to teratogenesis in this way. However, the problem with case reports is that they may be showing nothing more than a chance association, and caution must be exercised in their interpretation. Case studies are more secure in that they describe several patients where the same drug and malformation were linked: phenytoin and the retinoids were found to be teratogenic in this way. Epidemiological studies are of two major types: cohort studies which prospectively study exposed and unexposed groups, and case-control studies which retrospectively compare the pregnancies of abnormal and normal offspring. So far as teratogenesis is concerned, case-control studies are the norm because of the size and expense of cohort studies. The relationship between diethylstilboestrol use in the first trimester and vaginal adenocarcinoma in teenage offspring was found in a case-control study.

Among drugs that might be prescribed in the first trimester, those used in the treatment of nausea and vomiting and those used to prevent malaria deserve special mention because they illustrate important principles.

Antiemetic drugs in the first trimester

Most cases of morning sickness do not require treatment. However, some do and the drug about which most information is available was withdrawn from the market in 1983 in view of mounting public concern about its safety. This drug was a mixture of doxylamine succinate and pyridoxine hydrochloride and was marketed as Debendox® or Bendectin®. Despite having been used by over 30 million pregnant women over a quarter of a century, and notwithstanding carefully designed clinical trials suggesting that the drug was not teratogenic, individual case reports linking the use of the drug to fetal abnormality were given considerable publicity and led to its withdrawal. In view of the extremely high number of exposures, many chance associations between drug use and fetal abnormality were inevitable. Among possible alternatives, promethazine, cyclizine, or metoclopramide appear not to be teratogenic in the human.

The Debendox® saga illustrated that in an emotional area such as the use of drugs during pregnancy, well-chosen and carefully presented anecdotes can be more powerful than a substantial body of scientific data carefully accumulated over many years.

Malarial prophylaxis

Proguanil has a long record of safe use in pregnancy. However, in some areas use of chloroquine or a pyrimethamine/sulphonamide combination is necessary because of proguanil resistance. Currently available evidence suggests that chloroquine may cause a very small increase in birth defects: in one study 169 infants whose mothers took chloroquine base 300 mg once weekly were compared with 454 children whose mothers took no drug. The treated group gave rise to 1.2 per cent abnormal babies compared to 0.9 per cent in the controls: not a significant difference, but the study was too small to detect anything less than a five-fold increase in abnormality rate. Pyrimethamine/sulphonamide has not been associated with abnormality in the human but, being a folate antagonist, the possibility exists. In contrast to these minimal or theoretical risks, malaria presents a major risk to the health and life of both mother and baby, particularly when an expatriate woman is travelling in an endemic area.

While no one wishes to cause harm to the baby by prescribing a drug during pregnancy, equally it is important that harm does not befall mother or baby because treatment has been withheld.

Prescribing later in pregnancy

Beyond organogenesis, the fetus undergoes growth and development. The scope for producing anatomical defects has largely gone, exceptions being premature closure of the ductus arteriosus caused by indomethacin and bleeding into the fetal brain produced by warfarin. Growth and function tend to be the targets of drug adverse effects for the remainder of the pregnancy.

Angiotensin converting enzyme (ACE) inhibitors

The use of ACE inhibitors during the second and third trimesters has repeatedly been associated with oligohydramnios and neonatal anuria. Some series have put the perinatal mortality as high as 10 per cent, although over-reporting of poor outcomes has probably inflated this figure. None the less, a clear trend towards fetal or neonatal renal impairment when ACE inhibitors are used during pregnancy has been demonstrated. The mechanism is not known, but it seems probable that angiotensin II is necessary for fetal renal function. These drugs should not ordinarily be used in pregnancy. However, since ACE inhibitors are often used in the younger hypertensive, it is not uncommon to find a woman who has taken one through the first few weeks of pregnancy. This is not a reason for termination of pregnancy, but a detailed scan should be performed to exclude a rare skull ossification defect which may be associated with ACE inhibitors, and the woman should then be transferred to another drug, such as methyldopa.

Aspirin

Low-dose aspirin may prevent or delay pre-eclampsia in some women but may also lead to a small increase in the incidence of placental abruption. It is likely that low-dose aspirin exerts its platelet inhibiting effect entirely within the maternal portal circulation and is then metabolized in the liver with little active drug reaching the systemic circulation. Analgesic doses of aspirin have been shown to produce haemostatic problems in both mother and baby when given near the end of pregnancy. The problem seems to occur mainly when aspirin in a total dose of between 5 and 10 mg is given within 5 days before delivery. Under these circumstances a majority of mothers and almost all babies show some evidence of a bleeding tendency: in the newborn this can manifest as haematuria, cephalhaematoma, or subconjunctival haemorrhage. Since it is never quite clear when pregnancy will end, paracetamol is preferred as a mild analgesic in the third trimester.

Anticoagulants

The clinical use of anticoagulants during pregnancy is fully described in  Chapter 13.5 329. In addition to its teratogenic effects, warfarin has been associated with central nervous system abnormalities, such as microcephaly, when used later in the pregnancy. Bleeding into the fetal brain appears to be at least one mechanism and the problem occurs more commonly in women taking higher doses of warfarin.

Heparin does not harm the fetus, but is potentially damaging to the mother because of increased bone resorption. Osteoporosis has been recognized as a complication of heparin therapy for many years. The problem is not confined to pregnancy, but many of the reports have involved obstetric cases. The osteoporosis is dose related and typically occurs in a woman who has received more than 15 000 units/day of heparin for more than 6 months. The condition can be severe and lead to vertebral collapse.

Anticonvulsants

A neonatal coagulation defect has been associated with the use of phen- ytoin and barbiturates. The disorder occurs earlier than haemorrhagic disease of the newborn, usually within 24 h of birth, and can be serious. The condition has similarities to vitamin K deficiency and is accompanied by low concentrations of clotting factors II, VII, IX and X together with an increased concentration of a protein induced by the absence of vitamin K (PIVKA). Administration of vitamin K to the mother for 2 weeks prior to delivery has been reported to prevent the neonatal coagulation defect.

Indomethacin

Prostaglandins are involved in maintaining patency of the ductus arteriosus, and indomethacin has been shown to produce premature closure of the ductus. When indomethacin is given during pregnancy it is usually either for the suppression of preterm labour or in the management of rheumatoid arthritis. Echocardiographic studies of the fetal vasculature when indomethacin is being given for preterm labour have shown that ductal constriction can occur in 50 per cent of cases and appears within 12 h of drug administration. The constriction reverses within 24 h of indomethacin being discontinued. These findings suggest that when it is being used in the third trimester in the management of arthritis indomethacin should be discontinued at least 24 h before delivery. However, since it is never entirely clear when labour will begin, it is preferable to avoid indomethacin in the last weeks of pregnancy if possible.

&bgr;-Adrenoceptor antagonists and agonists

&bgr;-Blockers are used in pregnancy in the management of hypertensive diseases (see  Chapter 13.2 322), tachyarrhythmias, hypertrophic obstructive cardiomyopathy, and migraine. When given for relatively short periods of a few weeks these drugs have been found to lower maternal blood pressure with no adverse consequences for fetus or neonate. However, longer administration from early in pregnancy is associated in around 25 per cent of cases with intrauterine growth retardation, which can sometimes be severe. Methyldopa, which has a good safety record in pregnancy, is therefore the preferred drug in the management of essential hypertension during pregnancy.

&bgr;-Receptor agonists are used in the management of asthma and also in the suppression of preterm labour. A rare but potentially fatal association with the use of parenteral salbutamol or ritodrine in the management of preterm labour is maternal pulmonary oedema. Among various possible predisposing factors, fluid overload and the concomitant use of corticosteroids to accelerate fetal lung maturity are the most important. When &bgr;-receptor agonists are being used in preterm labour, the volume of fluid administered should be kept to a minimum and dextrose rather than saline should be used. Patients should be carefully monitored for the development of pulmonary oedema.

Corticosteroids

There are both maternal and fetal indications for the use of steroids during pregnancy. Women with conditions such as asthma, inflammatory bowel disease, or systemic lupus erythematosus, for instance, sometimes require therapy with prednisolone, as do those who have received a renal transplant. Betamethasone is used to accelerate fetal lung maturity in cases of spontaneous preterm labour or when early delivery is being performed because of worsening maternal disease, such as pre-eclampsia. There is no evidence that steroids are teratogenic in the human or that they significantly disturb the fetal hypothalamo-pituitary-adrenal axis. Suggestions that steroids can cause cleft palate are based on studies in rabbits and have never been confirmed in many human exposures. So far as the fetal adrenal is concerned, steroids vary in the extent to which they reach the fetal circulation. However, even those, such as betamethasone, which cross the placenta in sufficient amount to achieve a pharmacological effect on the fetal lung have been shown to have only a very transient effect on neonatal glucocorticoid levels, which become normal by 2 h following delivery.

Drugs and breast feeding

Most women now elect to breast feed their babies, and the majority will take a drug during this time. Iron, mild analgesics, antibiotics, laxatives, and hypnotics are the most commonly used. Much work has been performed on the pharmacokinetic aspects of breast feeding, but systematic studies on the effect of drug ingestion by the mother on her breast-fed baby are lacking.

Milk consists of fat globules suspended in an aqueous solution of protein and nutrients. Drugs move from plasma to milk by passive diffusion of the unionized and non-protein-bound fraction. Since breast milk has a slightly lower pH than plasma, drugs which cross most extensively into breast milk are lipid-soluble, poorly protein-bound, weak bases. However, even for drugs that do cross readily into breast milk, considerable dilution has already occurred in the mother. Thus when the concentration of a drug in breast milk and the volume of the milk consumed by the baby are translated into a dose it is often the case that the baby receives too little drug to have any detectable pharmacological effect. Some of the more commonly used drugs that, on the basis of experience, have a good safety record in breast-feeding mothers are listed in  Table 2 637.

It will be seen from this that many of the drugs that would be indicated for common medical problems in a breast-feeding mother are safe to use. Some qualification is needed about two of the drugs listed in the table. Oestrogen-containing oral contraceptives may suppress lactation if they are taken before the milk supply is well established and in some women may do so even after this time. Progestogen-only contraceptives do not influence lactation at any stage. Metronidazole is not harmful to the baby but is said to make the milk taste bitter and may therefore interfere with feeding.

Some drugs have been shown to affect the baby when ingested in breast milk; they are listed in  Table 3 638. There are several drugs for which theoretical risks exist, or for which isolated reports of serious adverse consequences have appeared. For example, aspirin is contraindicated in young children because of the possible association with Reye's syndrome and some authorities consider that the drug should therefore be avoided in women who are breast feeding. No evidence is available to support this view, but unless the use of aspirin is considered essential in a breast-feeding woman (and such an eventuality must be rare) then it is probably best avoided. Similarly, indomethacin has been associated with a neonatal convulsion in one case when used during lactation: a decision with regard to its appropriateness in any given patient would depend on the likelihood of real benefit accruing from its use.

Behavioural teratology

The most obvious consequences of a drug-induced fetal abnormality occur at or shortly after birth in the form of anatomical defects, and studies in teratology have largely concentrated on immediate pregnancy outcome. None the less, drugs can on occasion cause problems that become manifest only after several years. The most striking example is diethylstilboestrol which, when given during early pregnancy, can lead to adenocarcinoma of the vagina in the teenage offspring. In addition to late morphological effects, concern has been expressed that drugs given during pregnancy can influence behavioural development, although the available evidence is to the contrary.

Anticonvulsants

Several studies have claimed that the use of anticonvulsants during pregnancy is associated with impaired intellectual development of the children, but it is difficult to carry out studies in this area and the choice of control group is crucially important. When all children of treated epileptic mothers in a single hospital in Finland were studied prospectively, using the offspring of untreated epileptic mothers of the same social class as controls, no difference was found in intellectual development at the age of 5.5 years. At present it appears likely that, in the absence of any obvious morphological abnormality at birth, anticonvulsant use during pregnancy is not associated with impairment of intellectual development.

Antihypertensive drugs

One of the earliest trials into the treatment of hypertension during pregnancy involved a comparison of methyldopa with no treatment. The children underwent physical and psychomotor assessment at 4 and 7.5 years. The 4-year-old children from the treatment group had slightly smaller head circumference than their untreated controls, but there was no other physical or psychomotor difference. The evaluation at 7.5 years revealed no differences between the two groups. It is largely on this very well-conducted study that the reputation of methyldopa as a safe drug in pregnancy is based.

The effects on childhood development of atenolol and placebo have similarly shown no detrimental effects, a wide range of physical and psychomotor tests being performed on the children at the ages of 1 and 6 years.

Influence of pregnancy on dose requirements

While the emphasis on what drugs can do to the pregnancy is both understandable and appropriate, the physiological changes of pregnancy can have a clinically important influence on drug disposition and effect. The plasma concentrations of some drugs fall to a clinically important extent during pregnancy.

Among the many physiological changes in pregnancy, the most important from the standpoint of drugs are those that influence clearance. By the third trimester renal blood flow has nearly doubled and the activity of some, but not all, liver metabolic pathways is increased during pregnancy. A further factor tending to reduce drug concentrations is an increase in body water, with around an additional 7 litres being retained by the end of pregnancy.

The importance of these changes is well illustrated by the influence of pregnancy on anticonvulsant dose requirements. The concentrations of phenytoin, carbamazepine, phenobarbitone, and sodium valproate all decrease as pregnancy progresses. An increase in systemic clearance is the main reason—for example the clearance of phenytoin increases by over 100 per cent by the third trimester—with an increased volume of distribution making a further contribution. An example of the influence of pregnancy on the concentration of phenytoin is shown in  Fig. 1 1240. The reduction in anticonvulsant concentration can be substantial and if the dose is not increased then seizure control may be lost. Long before the advent of therapeutic drug monitoring it was recognized that seizure frequency in epileptics on treatment increased during pregnancy: subtherapeutic plasma drug concentrations will have been largely responsible. Drug levels should be monitored monthly during pregnancy and a falling level should initiate an increase in dose.

The physiological changes of pregnancy resolve in the 6 weeks following delivery, and there is a progressive return to pre-pregnancy dose requirements during this time.

Not all drugs metabolized in the liver show reductions in plasma concentration during pregnancy. For example, the clearance of propranolol is unchanged. This is presumably because the rate of propranolol clearance is determined by liver blood flow which is not altered by pregnancy.

Since renal blood flow increases during pregnancy, the clearance of drugs eliminated by this route would also be expected to increase. Lithium clearance doubles during pregnancy and dose increases, guided by drug-level monitoring, are likely to be needed. Dose requirements fall rapidly following delivery and care must be taken to avoid the development of toxicity. The clearance of ampicillin nearly doubles during pregnancy. Formal pharmacokinetic studies have not been performed with cephalosporins, but plasma levels of around 50 per cent of those found in non-pregnant subjects have been reported. In contrast to drugs with a reasonably well-defined therapeutic range, the falling plasma levels of penicillin or cephalosporin antibiotics are of less obvious significance. However, it seems prudent to give doses at the higher end of the recommended range when using these agents to treat systemic infections during pregnancy.

Drug protein binding in pregnancy

The protein binding of drugs is also altered by pregnancy. The mechanism is not fully understood, since although the concentration of albumin falls substantially in a normal pregnancy there is not, for all drugs, a correlation between the concentration of albumin and the free fraction of the drug. The free and pharmacologically active concentration of anticonvulsants is increased in pregnancy by 30 to 50 per cent, which has consequences for the interpretation of plasma drug levels.

Therapeutic drug monitoring during pregnancy

In general, whenever therapeutic drug monitoring would ordinarily be used in the non-pregnant woman, drug levels should be monitored monthly during pregnancy. While therapeutic ranges are imprecise, they do provide a useful guide to management. In the case of anticonvulsants, a useful clinical guideline is to assume that if control has been good before pregnancy at a particular level, and if the plasma concentration is falling substantially below that level as the result of pregnancy, then the dose should be increased. Waiting for a seizure to occur is unacceptable: women die from poorly controlled epilepsy in pregnancy.

Since the free fraction of anticonvulsants increases during pregnancy, the interpretation of drug levels needs careful consideration. Most laboratories report the total (bound plus unbound) drug concentration and this may be misleading since the proportion of unbound drug increases. Given that interpretation of drug levels is an imprecise science, a pragmatic approach to the problem is not to allow drug levels to fall below the lower third of the non-pregnant therapeutic range. Alternatively, saliva samples can be used to guide treatment, since these have been shown to correlate well with the plasma concentration of unbound drug.

 haematology, (ed. E.A. Letsky, I.M. Hann, and B.E.S. Gibson), pp. 285-314. Baillière Tindall, London.